Talk about something coming out of left field. Chronic fatigue syndrome (ME/CFS) isn’t the only condition that produces odd and puzzling responses to exercise. It turns out that people with rheumatoid arthritis (RA) have their own mysterious problems with exercise.
Exercise intolerance doesn’t just occur in ME/CFS. It’s also found in rheumatoid arthritis.
That doesn’t make sense. Yes, the swollen and painful joints found in RA present impediments to exercise but the joints aren’t the problem for people. People with RA find that exercise – often thought of as a universal healer – leaves them feeling “drained” and fatigued. Just as people with ME/CFS do, people with RA are exhibiting some sort of systemic exercise intolerance.
Fatigue is a big – and mysterious – issue in RA as well. Fatigue is common, yet the medications which improve the joint problems in RA have small or quite modest effects on fatigue. Despite the “the tremendous impact of fatigue on patient health and quality of life”, the consensus seems to be that fatigue is not a product of the disease itself but is caused by outside factors such as “obesity, physical inactivity, sleep disturbance, and depression”. Indeed, little research has attempted to understand the cause of fatigue in RA, and things like exercise, cognitive behavioral therapy, and mindfulness are recommended to treat it.
(A large, two-year UK CBT trial found that CBT was found to be helpful by patients but produced only moderate results (19% reduction in fatigue and self-care) at best. Persistent fatigue was still present.)
If RA is an autoimmune/inflammatory disease that attacks the joints, why are exercise intolerance and fatigue so common? The not-so-obvious answer is that RA is not just an immune disease that attacks the joints. It’s an immune disease that does other things as well -and that includes producing a lot of fatigue, and some kind of exercise intolerance.
That makes it very interesting for people with ME/CFS.
The Study
“…these differences suggest that sympathetic overactivation may be a hallmark in RA pathophysiology.” The authors
A recent Brazilian study, “Increased Sympathetic and Hemodynamic Responses to Exercise and Muscle Metaboreflex Activation in Post-menopausal Women with Rheumatoid Arthritis“, that got notice in the New York Times (“Why Exercise Can Be So Draining in Rheumatoid Arthritis“) uncovered some interesting parallels and differences between RA and ME/CFS.
A hyperactive sympathetic nervous system (SNS) that can impact everything from sleep to pain to exercise intolerance is found in both. Besides the high rates of SNS activity at rest, studies indicate that people with RA have trouble turning their SNS off, leaving their heart rates and blood pressures elevated after exercise. One metareview simply states that RA is a disease characterized by “parasympathetic autonomic dysfunction which is related to inflammation”. The autonomic problems found in RA are believed to be at least partly responsible for the increased risk of cardiovascular diseases found in RA.
This study took 43 older women (33 with, and 10 without RA), drew their blood, gave them questionnaires, and tested their blood pressure. They also embedded small sensors in their muscles that assessed the metabolites produced by the muscles, before, during, and after exercise. The exercise, itself, was considered “light”, and consisted of a series of isometric leg extensions for 3 minutes at 30% of their maximal capacity.
As expected, the RA patients’ sympathetic nervous systems were activated and their baroreflex response – which controls heart rate and blood pressure – was blunted during rest. The light exercise sent their already hyperactive sympathetic nervous system into overdrive – sending their blood pressure soaring – perhaps in an effort to drive more blood to the muscles. Those blood pressure spikes, the authors believe, may underlie some of the cardiovascular problems found in RA.
One of the study’s novel findings was the possibly central role the immune system may be playing. It appeared that pro and anti-inflammatory factors (IFN-y, IL-8, MCP-1 and TNFα, IL-1ra, and IL-10) produced by the muscles during the exercise session may be triggering the SNS hyperactivity.
The metaboreflex may be activated in different ways in RA and ME/CFS.
The Gist
- People with rheumatoid arthritis (RA) often feel drained and fatigued after exercise, but no one knows why.
- Drugs that improve RA do little to affect the fatigue or exercise problems in it. Some sort of systemic problem that hasn’t been addressed seems to be in play.
- Exercise triggers increased levels of sympathetic nervous system activity and causes blood pressure spikes that remain for unusually long periods.
- This study had RA patients engage in quite mild exercises (leg raises) while monitoring their cardiovascular responses. It also embedded tiny sensors in their muscles, which identified the metabolites the muscles were producing.
- Immune factors produced by the muscles during exercise were associated with the increased sympathetic nervous system (SNS) activity and blood pressure spikes.
- The “metaboreflex”, which occurs when muscles become overwhelmed by exercise, also was present. The metaboreflex sends signals to provide more blood flows to the muscle. It may also be triggering the SNS activity.
- The same metabolic receptors that Alan Light and company found were greatly upregulated in ME/CFS patients during exercise appeared to be upregulated in the RA patients as well.
- Thus far, it appears that different processes are tweaking those receptors, though. In ME/CFS, it appears that a breakdown in cellular energy production is, while in RA, it appears that inflammatory cytokines are.
- RA and ME/CFS, then, share similar biological processes (metaboreflex, high SNS activity) which trigger exercise intolerance. At their core, though, they may be quite different. Exercise intolerance is triggered in ME/CFS by problems with energy production, while it is triggered in RA by inflammation.
- The authors reported that they’d also found problems with exercise intolerance in long COVID and expect to be reporting on that soon.
These receptors sent signals to increase blood flows to the muscle – thus possibly triggering the sympathetic nervous system activation and increased blood pressure found.
Indeed, statistical analysis showed that the cytokine upregulation was “moderately associated” with the autonomic nervous system dysfunction (SNS activation) found. The sympathetic nervous system activation was, in turn, associated with increased pain.
The metaboreflex in RA, then, is being tricked by the immune system to portray a problem that’s not there. That “trick”, though, could have real consequences, as the authors believe it may be contributing to the cardiovascular problems found in RA.
ME/CFS and Rheumatoid Arthritis
Both conditions are associated with a hyperactive sympathetic nervous system, which in turn, is associated with increased levels of pain, fatigue, and blood circulation issues.
Wirth and Scheibenbogen, for instance, place heightened sympathetic nervous system activity at the core of ME/CFS. Increased sympathetic overdrive was also linked to an inability to complete an exercise program in ME/CFS. Likewise, sympathetic nervous system dominance has been documented in overtraining syndrome. High levels of systemic inflammation aren’t found in either of these conditions.
They are in RA. In the Brazilian study, the most impaired RA patients exhibited both increased sympathetic overdrive and depleted parasympathetic functioning – and the highest levels of inflammation.
Note that Alan Light’s MECFS gene expression and exercise study found the same metaboreflex receptor upregulation. Light proposed that high levels of muscle metabolites might be tweaking these receptors. Since then, numerous studies suggest that problems with energy production may exist.
The situation, at least at this point, appears to be markedly different in RA. Citing a 17-year-old study that did not find high levels of lactate in RA, the authors of the RA paper refused to go down the energy production rabbit hole. Instead, they proposed that inflammation was probably sensitizing the muscle metabolite receptors in RA. (This despite the fact that drugs that reduce inflammation in RA do little to improve RA patients’ fatigue.)
Thus, while the muscle metaboreflex appears to be turned on in both disorders – it appears that it’s turned on in different ways.
The result, while different in degree, is nevertheless similar – exercise activates the metaboreflex, which in turn, activates the SNS, producing pain and fatigue. Perhaps greater exercise intolerance in ME/CFS derives from the fact that it’s being produced both by energy production problems and sympathetic nervous system overdrive. In RA it’s produced mainly by sympathetic nervous system problems.
The Brazilian group has also found odd responses to exercise in people with long COVID.
There are probably only so many ways to produce exercise intolerance. Interestingly, RA and ME/CFS share some ways and not others. It’ll be fascinating to see the different permutations that crop up over time in different conditions.
The Brazilian authors managed to do something that I don’t believe has been done in ME/CFS: they embedded tiny sensors into the muscles and then tracked the changes that occurred in the muscles as the RA patients exercised.
While we don’t know what that would show in MECFS, we may soon get the next best thing. Dr. Roschel, the senior author of the study, stated that their exercise studies in long-COVID patients have found that “they also present abnormal cardiorespiratory responses to exercise“. Expect studies on that juicy topic to be published soon.
I think that vast majority of disease processes are caused by inflammation first, which then leads to an imbalance in energy availability and energy expenditure as a consequence.
Here is a study that shows this:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932180/
“In this narrative review, we discuss how chronic low-grade inflammation can lead to reduced cellular-energy availability. Low-grade inflammation induces a metabolic switch from energy-efficient oxidative phosphorylation to fast-acting, but less efficient, aerobic glycolytic energy production; increases reactive oxygen species; and reduces insulin sensitivity. These effects result in reduced glucose availability and, thereby, reduced cellular energy.”
I have had ME for 10 years.
I am treated with immunosuppressants. The drugs I take – prednisone and azathioprine- are used to treat RA. They help me a lot. With out them I am bedridden. With them I require 3-4 hours bedrest in the afternoon.
Interestingly, although my RA, sed rate, and c reactive protein are always normal, my d-dimer is always elevated. D-dimer is a measure of inflammation (in addition to measuring by products of blood clots).
How did you get prescribed those medications? I think my son with ME/CFS would benefit from trialing methotrexate or a biologic, but I’m not sure how to get a rheumatologist to take this idea seriously. This child has moderate/severe me/cfs, and interestingly his older brother has Spondyloarthritis and has hugely improved with Humira injections.
Time will tell. It seems strange that anything characterized as low-grade could cause the incredible functional problems in ME/CFS but there may be problems in ME/CFS which magnify the inflammations impact and cause it to target energy production. In any case, it’s good to have well known researchers like Robert Dantzer looking and writing about ME/CFS.
My Chronic Fatigue, once recognized still was ignored or left at the door. I do have Rheumatoid arthritis, Type2 diabetic, hypothyroid, although all are held within limits by medication my fatigue limits my employment – I can sleep 12 hrs a night and then 13-15 on the weekends, and still not be able to move…..
Cort what leads you to dismiss systemic inflammation as a cause of exercise intolerance in CFS? I thought there are markers of inflammation in CFS, even if they aren’t major. Maybe CFS is an illness where there is a disproportionate physiological response to inflammation, even fairly minor levels of inflammation.
What I find interesting is that curcumin is the only thing that has helped my exercise intolerance, and quite significantly.
I’m not dismissing it. I’m more questioning it than anything. On a gut level I find it strange that anything characterized as low-grade could cause ME/CFS. Of course, this is a strange disease (lol) so who knows. I think I agreed with your conjecture – that the effect of low grade inflammation could be magnified in ME/CFS.
Then again while anti-inflammatories may help some people to some extent they don’t seem to be the answer for most of us. Of course new or different kinds of anti-inflammatories might better target what is happening in ME/CFS.
It’s been obvious to me for a kong time that CFS is autoimmune in origin, and this cements that further for me.
I wish all the disparate and often fanciful non-autoimmune research could be put in the trashcan and that all efforts be put into autoimmune research.
*long
I began my road to constant exhaustion and pain (now called Fibromyalgia and ME/CFS when I had mono after being mugged in 2006. I got tired & had brain fog. Then I had surgery, and it got worse. Then I had COVID 3/20 and it got worse. Then, I had a knee replacement in 10/21, and six weeks after surgery, woke up in writhing pain throughout my body, and I have to plan appointments & exercise because I know I’ll need to spend a couple of days in bed after. I believe it’s going to come out that we ME/CFS sufferers already had one virus like Epstein-Barr in us, and COVID overtaxed our guts and sent our immune systems into overdrive.
Develop ANTI-VIRAL DRUGS to kill the Epstein-Barr virus, and I bet we will all be better able to function.
I concure! LongCovid of March 2020 made my #mecfs since June 17 2001 so much worse that I am now in #SkilledNursing facility since 012/21. Where I got Omicron in Jan23 all worse still, and #RSV in Dec23. It’s bad. LTC facilities aren’t prepared for fancy illnesses like ours and it’s been a NOISY HELL for me. Avoid at all costs! You sound soon like me, plus that EBV thought at the end!! Yes, solve EBV and all women of this World will be much healthier.
Fluge and Mella just put forth a hypothesis paper that focuses on autoantibodies. https://www.jci.org/articles/view/150377 Wirth and Scheibenbogen’s hypotheses have a central autoimmune component. Time will tell but that idea seems to be getting more attention.
Thanks, that sounds like quite a compelling theory from Fluge et al
Cort it has been very interesting to me that over the past few days I have been reading about’ “non-classical monocyte activation” in Post COVID long haul syndrome causing an inflammatory response in the microvascular endothelial cells as well as MAST cell Activation syndrome. Exercise also induces this reaction in this population.
The paper below is still unreviewed but it has intrigued me that Dr Bruce Patterson and Colleagues may be coming to some conclusions for Long Haul COVID patients that may prove relevant for the ME/CFS population.
https://www.biorxiv.org/content/10.1101/2021.06.25.449905v2.full
Any thoughts??
It seems RA may show some further similarities
– First 10yrs lymphopenia & high cytokines
– Then 2012 a shift happened (th1/th2?) leukocytosis with monocytosis (diagnosed but Left unexplained), eosinophilia & basophilia & high cd19 Bcells).
– Latest tests eosinophilia & basophilia remain & Bcells & T4 cells high
Unexplained also.
(Being looked at by an haematologist atm.)
Interesting:
– both basophils & eosinophils have mastcell properties.
– Bcells & T4 cells (also high) are linked & produce cytokines.
Some of the RA cytokines mentioned are high WITHOUT exercise.
– Bcells are linked to auto-immunity
To me? Whatever it’s called what I have? This is low grade inflammation and (auto-)immune dysregulation and a metabolic disease all at once.
– the CNS hyperactivity is not only there when there’s exertion. It’s always there. Like a switch that won’t go “off”.
Exerting (not exercise since that’s not possible) makes it worse.
The hyper CNS state is even more pronounced & leads to worsening of feeling ill (cytokines?), muscle pain, joint pain, toxic head (brainfog & cognitive impairment), utter utter exhaustion … disproportionate (hell) to the ‘exertion’ (having friends over for instance).
Don’t get why higher cytokines in ME (not only in RA) during & after ‘exercise’ aren’t mentioned?
Studies enough out there.
And then there’s lactate also …
It’s good to look into other illnesses but going from “fatigued to severe fatigue when exercising” is not comparable to
“utter exhaustion + hyper CNS
ALL THE TIME“ in ME.
Doing something very small (aerobic, anaerobic, talking, sensory insult, …) can lead pwME into a total systemic breakdown. Lasting very long.
Systemic breakdown being:
Neuro-(auto)-immune-CNS-metabolic-cytokine crash.
Totally impossible to do anything or see or hear anyone.
Not comparable to ‘very fatigued’.
Interesting article.
But I’m missing a few things about how much “more” ME is.
Even when you do not exert yourself.
Hence, I’m not a fan of “fatigue” in descriptions of ME.
-Low grade long lasting inflammation (D-dimer like someone said + cytokines),
-immune dysregulation (th1/th2 shift),
-CNS auto-immunity (scheibenbogen muscarin & adrenergic autoAbs)
-Mitochondrial defragmentation (prusty) (What’s that “factor x” in our blood that even makes healthy cells break down?)
-And in a subgroup proof of brain inflammation via PET-MRS (younger & others).
Post-infectious disease would still fit the bill the most (neurothropic pathogens) to explain all of this imo.
We need csf fluid & biopsies (stomach, gut, muscles … ) looked at too.
Excellent comment, Elsanna. What a great synopsis, and excellent questions.
I appreciated your points here:
“– the CNS hyperactivity is not only there when there’s exertion. It’s always there. Like a switch that won’t go “off”.
Exerting (not exercise since that’s not possible) makes it worse.”
… and this:
“(What’s that “factor x” in our blood that even makes healthy cells break down?)”
If can sometimes feel like examinations of our disease (or basket of diseases, at is were) and resulting theories fit ‘the blind men describing an elephant’ trope, when important previous findings aren’t included in newer studies nor included in new theories. Especially when the resulting treatments help symptom A, but worsen symptoms X, Y, and Z. Or help subgroup A, but worsen others with the disease.
Unfortunately, except for like IL-10 and perhaps TGF-B (?), cytokine results have been all over the map. In fact, I think, at least this point, there isn’t much evidence of systemic inflammation which is a problem as virtually everyone has thought that given the infectious triggers and the symptoms associated with “sickness behavior” that cytokine levels should be sky high.
It’s possible – and certainly Jarred Younger has brought up this point – that the microglial cells in the brain have become so sensitized that they’re getting activated by very small insults….That’s one way that low grade inflammation could produce problems. Indeed, I believe the type of neuroinflammation found in ME/CFS would probably be categorized as “low-grade” but it is also quite widespread. The reason I think it would be categorized as low-grade is because it wasn’t until recently that we had the technology that could pick it up.
The basal ganglia can also become sensitized so that they respond to low levels of inflammation as well.
“It’s possible – and certainly Jarred Younger has brought up this point – that the microglial cells in the brain have become so sensitized that they’re getting activated by very small insults….That’s one way that low grade inflammation could produce problems.”
Cort, isn’t this were the dauer theories might fit in? i.e. that the wide-spread but low-grade (as least from the perspective of current technology’s ability to measure) inflammation is being kept in check by our dauer-like state whose purpose is to protect us – hence certain systems “getting activated by very small insults”? And that, as has been asserted on here recently by some researchers, that we shouldn’t be casually just trying to get people out of that dauer-like state without understanding why it’s there and what it may be trying to protect us from?
I’m reading about Patterson now. There are the endothelial cells and the blood vessels again! Loved seeing that. For years I’ve this feeling the blood vessels must be involved. He also has a fascinating take on exercise intolerance. That guy is really getting around. A blog is coming up.
I agree. Scheibenbogen also have a very interesting study. I think you know it. -:) Don’t forget the redbloodcells and the bloodthickness.
https://pubmed.ncbi.nlm.nih.gov/32154656/
I look forward to your new blog-:)
So glad there is discussion of this article. It really struck me as potentially pertinent. Elsanna thanks for your description of your symptoms. I have has ME for over 45 years and guess that really makes me a LONG HAULER. I find my CNS disturbance of no “OFF” switch more emphasised post exertion/even thinking/ talking for a period of time not just physical.
Cort what I hope out of these studies like those done by Bruce Patterson is doing is that people suffering other types of viral/bacterial insults have access to this type of testing in the early days. I am sure glial cell activation is there as Younger has pointed out. For me Low Dose Naltrexone has been a big help
I was just going to say the same thing that Dr. Bruce Patterson has really entered the scene I feel like for Long COVID & possible answers for so many of us.
His background is incredibly impressive, so I’m happy to have another brilliant mind in the post-viral sequelae field.
Agreed….the more eyes on this the better.
Yes, Dr. Patterson and his implication of monocytes in these fatigue syndromes has been coming up a lot lately. If you look up I-Recover/FLCCC, he even has treatment protocol for long haul Covid.
Being in the Ehlers-Danlos crowd, I can say that one side or the other of 80% of EDSers have some sort of major fatigue problem. Autoimmune disorders, like RA, are also not an uncommon comorbidity for EDSers too. I find this connection intriguing. Stanford’s Chronic Fatigue clinic has a rather large contingency of EDSers as well. Mast Cell Activation Syndrome is also frequently implicated in both EDS and ME/CFS. I do wonder if it comes up in RA.
Now, this is a recent article/overview about pharmacological treatments for ME/CFS I thought I’d share; https://reader.elsevier.com/reader/sd/pii/S1043661821000487?token=8DCCFBA2E60C191D2A2D24F99E9E3C0B5E36BC1B049FECB5D668009C8A197C41C67A67404983853D870F98ABE96BE5EF&originRegion=us-east-1&originCreation=20210720180507
It also gives a research ‘overview’ too which is good to remember when considering the question of what exactly is causing our problem. Subsets?
And one more development is that Norris Labs is sending out press releases and videos about their identification of the underlying gene implicated in Hypermobile Ehlers-Danlos. Lest you all get too excited, they have identified it in one large family and so their discovery may not apply to everyone. Dr. Norris speculated that ultimately EDS is polygenetic. The currently unnamed gene is hinted to be involved with fibroblast growth factors and cell division.
I just hate it when researchers tease doctors and patients with some major discovery they can’t yet name…
Thank you Nancy B. I am also in the EDS basket too, though mildly and it was diagnosed last of all. I have a strong family history of ME/CFS and EDS though, through 3 generations. This was looked at by and Australian team many years ago now.
Thank you for the Research Article
I forgot to add that although I didn’t make the cut for POTS, it was noted that I have hair triggered tachycardia. My mom who undoubtedly had EDS which I probably inherited from her, had RA too. And fatigue. Really, really bad fatigue…
So how common is it for ME/CFSers to also have autoimmune disorders? Perhaps the diagnostic criteria is weeding most of them out, so doctors aren’t looking at that possible connection…
That’s a great question. I don’t know but I encourage everyone to join the You+ME Patient Registry so we can get answers to questions like that.
Rheumatoid arthitis is caused by autoimmunity (subgroup). Cyclophosphamide helps these patients. The same drug is also helping ME/CFS patients.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201056/
Probably this link should have been posted in the last Health Rising blog, (but I hadn’t seen it yet). Anyway, it is a very good article about the problems of long-haulers accessing disability. It does mention ME/CFS too.
Sorry but it’s a dreary report, but well written;
https://time.com/6081876/covid-19-long-haulers-disability-benefits/
I was diagnosed with RA several years before I became ill with me/cfs, and in my experience, exercise was vital to controlling my RA pain and energy levels. I never experienced anything like PEM or crashes with RA (although I did have ongoing malaise/ flu-like fatigue and pain that could worsen with stress or overexertion- the worsening was nothing like the absolute crashes of me/cfs though). I also was not nearly as mentally affected with RA (I completed a grad degree before being properly diagnosed and medicated- the main trouble was physical I.e. typing papers) as with me/cfs. It’s difficult to explain the difference in words, but I just wanted to put my experience out there because I was surprised to see any type of pem associated with RA (I can see if I had tried to run a marathon with RA or something though that my inflammation probably would’ve gotten way out of hand, so maybe it’s a matter of degree since at my worst with me/cfs, walking to a mailbox would’ve sent me into a downward spiral).
Perhaps having RA made you susceptible to ME/CFS? I also have both, but since RA is related to gene expression, one would have this (or at least the potential to have it) from birth. I’ve always wondered how it is I lucked out with severe asthma, AERD, chronic allergies and sinusitis, endometriosis, fibromylgia, RA, MTHFR in addition to ME/CFS. I think they are actually all related, and it wasn’t until I had some very stressful triggers within a 6 month period that I got ME/CFS, however many people have the same triggers (emergency cesarean, H1N1, stressful move) and *don’t* develop ME/CFS. Perhaps the genetics or disease process of RA sort of wore your immune and or CNS down to the point that ME/CFS followed?
This could fit into Jeff Wood’s mechanical basis hypothesis. According to this paper 40-85% of people with RA have Atlantoaxial Instability: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4984819/
Wow….
Hm, I know people wirh RA and none if them seems to get significantly worse after exercise. But, who knows…
Exercise intolerance , even a similar pattern like PEM is apparently also described in certain Liver diseases but I do not have a source. A Dr told me that, and its not clear to me if he grasps what happens in ME.
But I found it interesting..
It would have been very interesting to compare what is found in these patients, too.
I could scream. Saw a neurologist who never heard of ME! Head of the department at a large well known hospital!